The use of glycosaminoglycans, and particularly of heparins, in anticoagulant and antithrombotic therapies is well known, while their use in the treatment of the collateral pathologies of diabetes, like diabetic nephropathy and diabetic neuropathy, is unknown.
Kanwar Y. S. et al., Sem. Nephrol., 5, 307, (1985) and Groggel G. C. et al., Kidney Int., 33, 517, (1988), recently produced evidence of the probable role of glycosaminoglycans in helping the integrity and the functioning of the renal cells.
Moreover, Canfield J. P. et al., Lab. Invest., 39, 505, (1978), previously showed a decrease of glycosaminoglycans of membrane in many conditions of nephropathy, while Baggio B. et al., Nephron., 43, 187, (1986) showed this decrease through an increased urinary elimination of glycosaminoglycans in diabetic, non-albuminuric, patients. This increased excretion of glycosaminoglycans in diabetic nephropathies, shown also by Partasarathy N. et al., Diabetes, 31, 738, (1982), recently suggested to Gambaro G. et al., Metabolism, 38, 419, (1989), the possibility of resorting to the determination of the amount of glycosaminoglycans excreted by urinary route as an analytical method more reliable than the microalbuminuria in the recognition of the nephropathy of diabetic origin.
Lastly, Diamond J. R. et al., Renal Physiol., 9, 366, (1986) and Parkerson M. B. et al., J. Clin. Invest., 81, 69, (1988), showed in animals the potential protective effect of heparin and its derivatives in models of experimental nephropathy not related to diabetic nephropathy, like chronic nephrosis from aminoglycosides and renal pathologies resulting from the subtotal renal ablation in the rat.
Pharmacological studies that show a possible role of exogenous glycosaminoglycans administered for prevention or therapy of diabetic glomerulopathy and diabetic nephropathy do not exist yet.
One object of the present invention is to provide a method for the prevention and therapy of diabetes nephropathy by the administration of an effective amount of a glycosaminoglycan, particularly of heparin and its derivatives obtained by depolymerization or by other chemical modifications like, for instance, O and/or N sulfation or desulfation, of the heparinic structure, of dermatan sulfate and its low molecular weight fractions.
Another object of the present invention is to provide a method for the therapy of diabetes neuropathy by the administration of an effective amount of a glycosaminoglycan, particularly of heparin and its derivatives obtained by depolymerization or by other chemical modifications like, for instance, O and/or N sulfation or desulfation, of the heparinic structure, of dermatan sulfate and its low molecular weight fractions.
Diabetic neuropathy is a disease that hits the nerves and the neurons of the peripheral nervous system of diabetic patients. This pathology is characterized by a progressive morphofunctional alteration of this system that starts with a reduced functioning of the nerves, noticeable by a lowered speed of conduction of the nervous impulse, and that gradually proceeds up to the degeneration of the nerves and the atrophy of the neurons. This event causes a gradual loss of the sensory capacities (pain, warmth etc.), a decrease of the muscolar strength and a serious degeneration of the autonomic nervous system. This latter complication is surely the most frequent among the complications caused by diabetes; as a matter of fact about 70%-80% of the diabetic patients suffers from gastrointestinal disorders caused by the bad functioning and the degeneration of the autonomic enteric system.
This complication is directly related to the degeneration of two intrinsec neuron factors of the intestinal wall. They are the system containing Met-Enkephalin and that containing Substance P. Met-Enkephalin controls the contraction of the sphincter between stomach and intestine and moreover is able to modulate the excitability of the other enteric neurons. Substance P is contracting, therefore it is one of the substances responsible for the intestinal motility.
Di Giulio A. M. et al., J. Neurosc. Res., 24, 355-61, (1989), recently demonstrated that these two neuron systems degenerate, with loss of Substance P and Met-Enkephalin in the intestinal zones of duodenum and jejunum, in the experimental diabetes caused by alloxan.
No bibliography exists up to now related to a possible implication of endogenous glycosaminoglycans in setting up the diabetic neuropathy and moreover pharmacological studies that show a possible role of the exogenous glycosaminoglycans administered with a prophylactic or therapeutic purpose in the neuropathy of diabetic origin do not exist.